Methods of treating or alleviating mental disorders and associated symptoms

ABSTRACT

The present invention relates generally to methods for the treatment and/or prophylaxis of mental illness involving administration of 10-HDA. More particularly, methods are taught herein for the treatment and/or prophylaxis of obsessive compulsive disorder, anxiety disorder or a condition characterised by one or more symptoms of a obsessive compulsive disorder or an anxiety disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation and claims the benefit of priority ofU.S. patent application Ser. No. 15/780,913, filed on Jun. 1, 2018,entitled “METHODS OF TREATING OR ALLEVIATING MENTAL DISORDERS ANDASSOCIATED SYMPTOMS” which is the National Stage of InternationalApplication No. PCT/IB2016/001853, filed Dec. 2, 2016, entitled “METHODSOF TREATING OR ALLEVIATING MENTAL DISORDERS AND ASSOCIATED SYMPTOMS,”which claims the benefit of priority of Australian ProvisionalApplication No. 2015905047, filed Dec. 4, 2015. The entire disclosuresof all these applications (including all attached documents) areincorporated by reference in their entireties for all purposes.

TECHNICAL FIELD

The present invention relates generally to methods for the treatmentand/or prophylaxis of mental disorders and associated symptoms. Inparticular, the methods of the present invention are particularly usefulin the treatment and/or prophylaxis of obsessive compulsive disorders,anxiety disorders and conditions characterised by one or more symptomsof obsessive compulsive disorders and anxiety disorders.

BACKGROUND OF THE INVENTION

Mental disorders are a broad class of potentially debilitatingconditions which can affect people of all ages. Obsessive compulsivedisorders and symptoms associated with obsessive compulsive disordersrepresent a subset of mental disorders characterised by obsessionsand/or compulsions, which result in distress and anxiety. Anxietydisorders and symptoms relating to anxiety represent a subset of mentaldisorders characterised by excessive fear and anxiety. Both obsessivecompulsive disorders and anxiety disorders can have significant mental,emotional, physical, and economic consequences for individuals.

Obsessive compulsive disorders (OCD) are a complex group of highlyvariable mental disorders; distinguished not by a single symptom, but bya multitude of characteristic symptoms. Symptoms typically appear beforethe age of thirty-five; and more commonly symptoms will appear beforethe age of twenty, and continue through adulthood. Itis estimated thatobsessive compulsive and related disorders will affect about 2.3% ofpeople at some point in their life. While males and females are equallyaffected by OCD and related disorders, male patients often develop OCDat a younger age and general exhibit more severe symptoms. Furthermore,it has been reported that female OCD patients exhibit worse symptomsduring menstruation, post-menopause or and/or within one month ofchildbirth, suggesting some degree of hormonal influence.

Current treatments for obsessive compulsive disorders aim to increasequality of life and functional independence as well as reduce associateddeficits and family distress. Typical treatment involves the use ofeducational or behavioural therapies. Outside of behavioural therapies,a number of different medications have been used, with varying degreesof success. Selective serotonin reuptake inhibitors (SSRIs) may be usedin conjunction with behavioural therapy to alleviate symptoms. However,40-60% of OCD-patients fail to respond to SSRI-monotherapy. Furthermore,atypical antipsychotics and dopamine antagonists have also been found tobe useful, when used in addition to an SSRI, in treatment-resistantcases. However, OCD patients often respond atypically to medications orthe prescribed medications may have other adverse side effects. In theabsence of treatment, the course of an obsessive compulsive disorder isusually chronic, however the nature and severity of symptoms may varyover time and/or in response to environmental triggers and cues.

Anxiety disorders and symptoms relating to anxiety in accordance withthe present invention may include, for example disorders that sharefeatures of excessive fear and anxiety and related behaviouraldisturbances. The emotions present in anxiety disorders range fromsimple nervousness to bouts of terror. Most anxiety disorders occur morefrequently in females than in males (approximately 2:1 ratio). Symptomsmay appear at any time, though for many patients, symptoms often appearin childhood. Treatment depends on the nature and severity of symptoms.However, treatment of anxiety disorders typical involves the use ofeducational or behavioural therapy, in conjunction with a number ofdifferent medications, such as antidepressants and anti-psychotics,including selective serotonin reuptake inhibitors (SSRis). Medication isoften associated with adverse side effects. In the absence of treatment,many anxiety disorders persist as chronic conditions.

Accordingly, there is an on-going need to develop new therapeutic agentsor methods of treating and/or preventing mental disorders and associatedsymptoms such as OCD and anxiety disorders.

SUMMARY OF THE INVENTION

The applicants of the present application have surprisingly found that10-hydroxy-2-decenoic acid (10-HDA), compositions containing 10-HDA, andpharmaceutically acceptable salts thereof, offer an effective therapyfor the treatment and/or prophylaxis of mental disorders, in particular,obsessive compulsive disorders and anxiety disorders.

10-HDA, also referred to as queen bee acid, is a fatty acid and keycomponent of royal jelly; a honey bee secretion used in the nutrition oflarvae and adult queens. In view of the alkene functional group, it isrecognised that 10-HDA may exist as either the trans or cis geometricisomers. These isomers may also be referred to as (E) or (Z) isomers,respectively.

Trans or (E)-10-hydroxy-2-decenoic acid has the following structure:

Cis or (Z)-10-hydroxy-2-decenoic acid has the following structure:

Throughout this specification reference to 10-HDA is intended to meanreference to each of the (E) isomer and (Z) isomer, as well as mixturesof the two isomers, unless otherwise specified.

In one aspect of the invention, there is provided a method for thetreatment and/or prophylaxis of a mental disorder, comprisingadministering to a mammal in need thereof an effective amount of10-hydroxy-2-decenoic acid or a pharmaceutically acceptable saltthereof, wherein the mental disorder is selected from an obsessivecompulsive disorder, an anxiety disorder or a condition characterised byone or more of symptoms of obsessive compulsive disorder or an anxietydisorder.

In one or more embodiments, the method of the present inventioncomprises administering an effective amount of trans10-hydroxy-2-decenoic acid or a pharmaceutically acceptable saltthereof.

In still other embodiments, the method of the present inventioncomprises administering an effective amount of cis 10-hydroxy-2-decenoicacid or a pharmaceutically acceptable salt thereof.

In further embodiments, the method of the present invention comprisesadministering an effective amount of a mixture of trans and cis10-hydroxy-2-decenoic acid or a pharmaceutically acceptable saltthereof.

In one aspect of the invention, there is provided a method for thetreatment and/or prophylaxis of a mental disorder, comprisingadministering to a mammal in need thereof a pharmaceutical compositioncomprising 10-hydroxy-2-decenoic acid, or a pharmaceutically acceptablesalt thereof, wherein the mental disorder is selected from an obsessivecompulsive disorder, an anxiety disorder or a condition characterised byone or more of symptoms of obsessive compulsive disorder or an anxietydisorder.

In one or more embodiments, the method of the present inventioncomprises administering a pharmaceutical composition comprising trans10-hydroxy-2-decenoic acid, or a pharmaceutically acceptable saltthereof. In one or more embodiments, the method of the present inventioncomprises administering a pharmaceutical composition comprising cis10-hydroxy-2-decenoic acid, or a pharmaceutically acceptable saltthereof. In one or more embodiments, the method of the present inventioncomprises administering a pharmaceutical composition comprising amixture of cis and trans 10-hydroxy-2-decenoic acid, or apharmaceutically acceptable salt thereof. In one or more embodiments,the method of the present invention comprises administering apharmaceutical composition comprising trans 10-hydroxy-2-decenoic acid,or a pharmaceutically acceptable salt thereof, wherein the trans10-hydroxy-2-decenoic acid is synthetic trans 10-hydroxy-2-decenoicacid.

In one or more embodiments, the mental disorder may be an obsessivecompulsive disorder, in particular an obsessive compulsive disorderselected from the group consisting of obsessive-compulsive disorder(OCD), body dysmorphic disorder, hoarding disorder, trichotillomania(hair-pulling disorder), excoriation (skin picking) disorder,substance/medication-induced obsessive-compulsive and related disorder,obsessive-compulsive and related disorder due to another medicalcondition, and other specified obsessive-compulsive and related disorderand unspecified obsessive-compulsive and related disorder (e.g.,body-focused repetitive behaviour disorder, obsessional jealousy).

In other embodiments, the mental disorder may be an anxiety disorder, inparticular, an anxiety disorder selected from the group consisting ofseparation anxiety disorder, selective mutism, phobias, social anxietydisorder (social phobia), panic disorder, panic attack specifier,agoraphobia, generalized anxiety disorder, substance/medication-inducedanxiety disorder, anxiety disorder due to another medical condition,other specified anxiety disorder, unspecified anxiety disorder.

In other aspects, 10-hydroxy-2-decenoic acid or a pharmaceuticallyacceptable salt thereof in accordance with the present invention may beadministered as a composition. In some embodiments, the composition maycomprise royal jelly, an extract of royal jelly, or a compositionderived from royal jelly. In other embodiments, the composition is notroyal jelly, an extract of royal jelly, nor a composition derived fromroyal jelly. In other embodiments, the 10-hydroxy-2-decenoic acid, or apharmaceutically acceptable salt thereof, is synthetic10-hydroxy-2-decenoic acid. In some embodiments, the10-hydroxy-2-decenoic acid, or a pharmaceutically acceptable saltthereof, in accordance with the present invention, is administered as acomposition consisting of 10-hydroxy-2-decenoic acid and at least onepharmaceutically acceptable excipient. In some embodiments, the10-hydroxy-2-decenoic acid, or a pharmaceutically acceptable saltthereof, in accordance with the present invention, is administered as acomposition consisting of trans 10-hydroxy-2-decenoic acid and at leastone pharmaceutically acceptable excipient. In some embodiments, the10-hydroxy-2-decenoic acid, or a pharmaceutically acceptable saltthereof, in accordance with the present invention, is administered as acomposition consisting of cis 10-hydroxy-2-decenoic acid and at leastone pharmaceutically acceptable excipient. In some embodiments, the10-hydroxy-2-decenoic acid, or a pharmaceutically acceptable saltthereof, in accordance with the present invention, is administered as acomposition consisting of a mixture of trans and cis10-hydroxy-2-decenoic acid and at least one pharmaceutically acceptableexcipient.

In still other aspects, the present invention provides the use of10-hydroxy-2-decenoic acid or a pharmaceutically acceptable salt thereofin the preparation of a medicament for the treatment and/or prophylaxisof mental disorders, wherein the mental disorder is selected from anobsessive compulsive disorder, an anxiety disorder or a conditioncharacterised by one or more of symptoms of obsessive compulsivedisorder or an anxiety disorder.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs.

The reference to any prior art in this specification is not, and shouldnot be taken as, an acknowledgment or any form of suggestion that thatprior art forms part of the common general knowledge.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1: Obsessive compulsive-like behaviour of aromatase knockout (ArKO)and wildtype (WT) mice; A. Social interaction study; B. Ultrasonicvocalization; wildtype (WT); ArKO mice (KO).

FIG. 2: Obsessive compulsive-like behaviour of aromatase knockout (ArKO)mice. A. Running wheel activity over two consecutive nights in 6-monthold males. B. Ambulatory activity of 6-month old male animals over fourdays and four nights. C. Running wheel activity of 6-month old females.D. Ambulatory activity of 6-month old females; wildtype (WT), ArKO mice(KO), 17 β-estradiol treated ArKO mice (KO+E2), placebo treated ArKOmice (KO+p).

FIG. 3: Obsessive compulsive-like behaviour of aromatase knockout (ArKO)mice; C. Frequency of initiation of grooming of male animals over a20-min period post water mist spray. Duration of grooming of maleanimals over 20-min time period post water mist spray. E. Frequency ofinitiation of grooming of 6 month-old female animals during a 20-minperiod post water mist spray. F. Duration of grooming of 6 month-oldfemale animals over a 20-min period post water mist spray; wildtype(WT), ArKO mice (KO), estradiol treated ArKO mice (KO+E2), placebotreated ArKO mice (KO+p).

FIG. 4: Treatment of aromatase knockout (ArKO) mice with 10-HDA;duration of grooming of male animals over a 10-min period post-watermist spray; before treatment with 10-HDA and after treatment with10-HDA.

FIG. 5: Box plots of expression levels of (a) dynamin 3 and (b)5-hydroxytryptamine (serotonin) receptor 2C transcripts in primarycortical cultures with vehicle or 10-HDA treatments as determined byNext Generation Sequencing.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein is a method for treatment and/or prophylaxis of a mentaldisorder, comprising administering to a mammal in need thereof aneffective amount of 10-hydroxy-2-decenoic acid (10-HDA) or apharmaceutically acceptable salt thereof.

As highlighted above, in view of the alkene functional group, it isrecognised that 10-HDA may exist as either the trans or cis isomers, ormixtures thereof. Accordingly, in some embodiments, the methods and usesdescribed herein comprise administering an effective amount of trans10-hydroxy-2-decenoic acid or a pharmaceutically acceptable saltthereof. In still other embodiments, the methods and uses describedherein comprise administering an effective amount of cis10-hydroxy-2-decenoic acid or a pharmaceutically acceptable saltthereof. In further embodiments, the methods and uses described hereincomprise administering an effective amount of a mixture of10-hydroxy-2-decenoic acid or pharmaceutically acceptable salts thereof.

In some embodiments the 10-hydroxy-2-decenoic acid is synthetic10-hydroxy-2-decenoic acid.

In some embodiments the 10-hydroxy-2-decenoic acid is purified10-hydroxy-2-decenoic acid.

In some embodiments the 10-hydroxy-2-decenoic acid is isolated andpurified 10-hydroxy-2-decenoic acid.

In some embodiments the 10-hydroxy-2-decenoic acid is not derived fromroyal jelly.

In some embodiments the 10-hydroxy-2-decenoic acid is administered as apharmaceutical composition. In some embodiments the pharmaceuticalcomposition comprises at least one pharmaceutically acceptableexcipient. In some embodiments the pharmaceutical composition comprises10-hydroxy-2-decenoic acid and at least one pharmaceutically acceptableexcipient. In some embodiments the pharmaceutical composition consistsof 10-hydroxy-2-decenoic acid and at least one pharmaceuticallyacceptable excipient. In some embodiments the pharmaceutical compositionconsists of 10-hydroxy-2-decenoic acid as the active ingredient, and atleast one pharmaceutically acceptable excipient. In some embodiments thepharmaceutical composition does not provoke an immunogenic response.

The methods described herein advantageously provide a reduction of coresymptoms of mental disorders, in particular the symptoms associated witha mental disorder such as an obsessive compulsive disorder or an anxietydisorder. In some aspects, the methods of the present inventionadvantageously provide a reduction in the severity of symptoms of OCD,for example, repetitive behaviours.

In some embodiments, the person is currently in need of such treatmentas determined by a qualified physician. In other embodiments, thecompound is administered in a prophylactic sense.

References to a “mental disorder” or a “mental illness”, are usedinterchangeably, and should be understood as a reference to a conditioncharacterised by behavioural, cognitive and/or emotional patterns ordisturbances which influence or reduce an individual's capacity tofunction in ordinary life.

In one embodiment, said mental disorder is a condition which ischaracterised by one or more symptoms of an obsessive compulsivedisorder or an anxiety disorder, including obsessive compulsive disorderor generalised anxiety disorder.

The term obsessive compulsive disorders (OCDs), as used herein, would beclear to persons skilled in the art and includes obsessive-compulsivedisorder (OCD), body dysmorphic disorder, hoarding disorder,trichotillomania (hair-pulling disorder), excoriation (skin-picking)disorder, substance/medication-induced obsessive-compulsive and relateddisorder, obsessive-compulsive and related disorder due to anothermedical condition, and other specified obsessive-compulsive and relateddisorder and unspecified obsessive-compulsive and related disorder(e.g., body-focused repetitive behaviour disorder, obsessionaljealousy), as defined in the Diagnostic and Statistical Manual of MentalDisorders 5 (DSM-5) published in May 2013. The Diagnostic andStatistical Manual of Mental Disorders 5 outlines diagnose of OCD by thepresence of obsessions, compulsions, or both. Furthermore, theobsessions or compulsions are time-consuming (e.g., take more than Ihour per day) or cause clinically significant distress or impairment insocial, occupational, or other important areas of functioning.

The Diagnostic and Statistical Manual of Mental Disorders 5 outlinesthat obsessions are defined by:

-   -   1. Recurrent and persistent thoughts, urges, or images that are        experienced, at some time during the disturbance, as intrusive        and unwanted, and that in most individuals cause marked anxiety        or distress.    -   2. The individual attempts to ignore or suppress such thoughts,        urges, or images, or to neutralize them with some other thought        or action (i.e., by performing a compulsion).

Furthermore, the Diagnostic and Statistical Manual of Mental Disorders 5outlines that compulsions are defined by:

-   -   1. Repetitive behaviours (e.g., hand washing, ordering,        checking) or mental acts (e.g., praying, counting, repeating        words silently) that the individual feels driven to perform in        response to an obsession or according to rules that must be        applied rigidly.    -   2. The behaviours or mental acts are aimed at preventing or        reducing anxiety or distress, or preventing some dreaded event        or situation; however, these behaviours or mental acts are not        connected in a realistic way with what they are designed to        neutralize or prevent, or are clearly excessive.

Reference to “symptoms characteristic of OCD” should be understood as areference to any one or more symptoms which may occur in an individualsuffering from OCD. These symptoms may be evident throughout the courseof the disorder or they may be evident only transiently or periodically.For example, an individual may exhibit severe repetitive behaviours(e.g., washing, checking) in response to specific environmental cues orstressors. It should also be understood that the subject symptoms maynot necessarily be exhibited by all individuals suffering from OCD. Forexample, some individuals may suffer from obsessions only, such aspersistent thoughts or urges in the absence of compulsions, such asrepetitive behaviours. However, for the purpose of the presentinvention, any such symptoms, irrespective of how many or few OCDpatients ever actually exhibit the given symptom, are encompassed bythis definition.

Obsessions are typically repetitive and persistent thoughts, images, orurges. Compulsions or rituals are repetitive behaviours or mental actsthat the individual feels driven to perform in response to an obsessionor according to rules that must be applied rigidly. Where compulsionsinvolve repetitive motions or behaviours, these may include actionswhich may be repeated over and over again. For example, an OCD patientwith repetitive and persistent thoughts of contamination (i.e. anobsession), might spend a lot of time cleaning (i.e. a compulsion).

Obsessions are not pleasurable or voluntary, but cause marked distressor anxiety in most individuals. Similarly, Compulsions are not done forpleasure, although some individuals experience relief from anxiety ordistress.

Obsessions and compulsions associated with OCD are typicallytime-consuming or cause clinically significant distress or impairment.It will be appreciated that the nature, frequency and severity ofobsessions and compulsions varies between individuals (e.g., some havemild to moderate symptoms i.e. 1-3 hours per day; others have nearlyconstant intrusive thoughts or compulsions). Typical examples ofobsessions and compulsions common to OCD include, but are not limitedto:

-   -   cleaning (contamination obsessions and cleaning compulsions);    -   symmetry (symmetry obsessions and repeating, ordering, and        counting compulsions);    -   forbidden or taboo thoughts (e.g., aggressive, sexual, or        religious obsessions and related compulsions); and    -   harm (e.g., fears of harm to oneself or others and checking        compulsions);    -   dysfunctional beliefs (e.g., inflated sense of responsibility,        tendency to overestimate threat; perfectionism and intolerance        of uncertainty; and/or over-importance of thoughts).

People with OCD often thrive on routine. A change in the normal patternof the day can cause severe anxiety and/or distress for an individualsuffering from OCD. They might “lose control” and have a “melt down” ortantrum, especially in response to environment triggers or where theperformance of a particular compulsion is interrupted. Furthermore, anindividual suffering from OCD may develop routines that could beperceived as unusual or unnecessary. For example, an individualsuffering from OCD may be convinced that the house will burn down if thestove is not checked 30 times. Deviation from these types of routinesmay cause severe anxiety and distress.

The term “anxiety disorders”, as used herein, would be clear to personsskilled in the art and includes disorders that share features ofexcessive fear and anxiety and related behavioural disturbances. Forexample, anxiety disorders may include separation anxiety disorder,selective mutism, specific phobia, social anxiety disorder (socialphobia), panic disorder, panic attack specifier, agoraphobia generalizedanxiety disorder, substance/medication-induced anxiety disorder, anxietydisorder due to another medical condition, other specified anxietydisorder, and/or unspecified anxiety disorder as defined in theDiagnostic and Statistical Manual of Mental Disorders 5 (DSM-5)published in May 2013.

Anxiety disorders share similar symptoms, but differ from one another inthe types of objects or situations that induce fear, anxiety, oravoidance behaviour, and the associated cognitive ideation. Fear isrecognised as the emotional response to real or perceived imminentthreat. Anxiety is recognised as anticipation of future threat. Overlapbetween the two states may exist in individuals suffering from anxietydisorders. It is generally recognised that anxiety disorders differ fromdevelopmentally normative fear or anxiety by being excessive orpersisting beyond developmentally appropriate periods. They differ fromtransient fear or anxiety, often stress-induced, by being persistent.

Examples of anxiety disorders include generalized anxiety disorder. TheDiagnostic and Statistical Manual of Mental Disorders 5 outlines thatgeneralized anxiety disorder is defined by:

-   -   excessive anxiety and worry (apprehensive expectation),        occurring more days than not for at least 6 months, about a        number of events or activities (such as work or school        performance);    -   individual finds it difficult to control the worry;    -   anxiety and worry may be associated with one or more of:        -   a. Restlessness or feeling keyed up or on edge,        -   b. Being easily fatigued,        -   c. Difficulty concentrating or mind going blank,        -   d. Irritability,        -   e. Muscle tension, and        -   f. Sleep disturbance (difficulty falling or staying asleep,            or restless, unsatisfying sleep or insomnia).    -   clinically significant distress or impairment in social,        occupational, or other important areas of functioning.

Reference to “symptoms characteristic of anxiety disorders” should beunderstood as a reference to any one or more symptoms which may occur inan individual suffering from an anxiety disorder. These symptoms may beevident throughout the course of the disorder or they may be evidentonly transiently or periodically. For example, an individual may exhibitsevere sleep disturbance (e.g., insomnia) in response to specificenvironmental cues or stressors. It should also be understood that thesubject symptoms may not necessarily be exhibited by all individualssuffering from anxiety disorder. For example, some individuals may relyon avoidance behaviours which may mask underlying symptoms of anxietyand fear. However, for the purpose of the present invention, any suchsymptoms, irrespective of how many or few anxiety disorder patients everactually exhibit the given symptom, are encompassed by this definition.

In addition to the fact that there may be significant variation betweenpatients suffering from mental disorders, such as anxiety disorders oranxiety disorders, in terms of which symptoms they exhibit, it shouldalso be understood that there are other mental disorders which are alsocharacterised by one or more of these symptoms. The obsessions andcompulsions exhibited by OCD patients, for example, may also commonly beobserved in patients with anxiety disorders; major depressive disorders;other obsessive-compulsive and related disorders, such as bodydysmorphic disorder, hoarding disorder, trichotillomania (hair-pullingdisorder); eating disorders; tics; psychotic disorders, such asdelusional disorder; compulsive-like behaviours; and/orobsessive-compulsive personality disorder. The fear and anxietyexhibited by anxiety disorder patients may be observed in patients withobsessive compulsive disorders, post-traumatic stress disorder andadjustment disorders, major depressive disorders, bipolar disorder,other psychotic disorders, social anxiety disorder, substance ormedication induced anxiety disorder. Accordingly, reference to acondition characterised by one or more symptoms characteristic of OCDand/or anxiety disorders should be understood as a reference to anymental disorder which is characterised by the presence of one or more ofthese symptoms.

Without wishing to be bound by theory, the present invention ispredicated in part on the inventors' observation that an AromataseKnockout mouse (ArKO) model may exhibit behavioural phenotypesreflective of some of the key diagnostic behaviours and symptoms of OCDdisorder. In particular, the inventors have demonstrated that the lackof a normal functioning aromatase will precipitate OCD-like repetitivebehavioural disturbances in a male Aromatase Knockout mouse (ArKO) mouse(Hill et al. (2007) Biol. Psychiatry; vol. 61 pp. 359-366, incorporatedherein by reference).

Still other behavioural phenotypes exhibited by the male ArKO mouse maybe reflective of some of the key diagnostic behaviours and symptoms ofanxiety disorders.

For example, some key behavioural disturbances observed in maleAromatase Knockout mice (ArKO) which are reflective of one or moresymptoms of OCD and anxiety disorders include, but are not limited to,compulsive wheel running, compulsive grooming, vocalisation deficit,and/or social interaction deficit. These and other behaviouraldisturbances are considered to be substantially similar to obsessionsand compulsions exhibited by human patients suffering from OCD, andfurthermore, may be indicative of anxiety and/or fear exhibited by humanpatients suffering from anxiety disorders.

The inventors have surprisingly found that the administration of 10-HDAto male ArKO mice alleviated one or more of the behaviouraldisturbances, including a reduction in wheel running and/or compulsivegrooming.

Accordingly, in one aspect, the present invention provides a methodtreating or alleviating a mental disorder.

In particular, in some embodiments, the present invention provides amethod of treating or alleviating an obsessive compulsive disorder, ananxiety disorder or a condition characterised by one or more symptoms ofobsessive compulsive disorder or an anxiety disorder.

Serotonin (5-hydroxytryptamine) receptor 2C (HTR2C) is a member of theserotonin receptor family of G-protein coupled receptors. HTR2Cexpression and activity has been shown to be modulated through RNAediting. J. Cheng et al. (2015) ChemMedChem 10(12): 1963-1967; K.Iwamoto et al. (2009) RNA Biology 6(3): 248-253. HTR2C is primarilyexpressed in the central nervous system (CNS) and has been implicated inseveral CNS disorders. J. Cheng et al. (2015) ChemMedChem 10(12):1963-1967. For example, modulators of HTR2C have been shown to havetherapeutic potential for schizophrenia, obesity, addiction, obsessivecompulsive disorder, and depression. J. Cheng et al. (2015) ChemMedChem10(12): 1963-1967; A Frisch et al. (2000) Eur Neuropsychopharmacol10(3): 205-209; F. Jenck et al. (1998) Expert Opin Investig Drugs 7(10):1587-1599. The role of HTR2C in the CNS has also been demonstrated usingHTR2C knockout mice. These mice exhibit behaviours such as over-eating,hyperexcitability, compulsive behaviour, and epileptic convulsions. J.M. Chou-Green et al. (2003) Physiol Behavior 78(4-5): 641-649; M. Tohdaet al. (2006) J Pharmacol Sci 100: 427-432.

Dynamin-3 (DNM3) is a member of the dynamin family of GTPases that areprimarily involved in membrane fission events. DNM3 is highly expressedin the CNS, being specifically enriched in the brain. B. Calabrese etal. (2015) Mol Cell Neurosci 68: 36-45; A Romeu et al. (2014) BMCResearch Notes 7: 188. Within the CNS, DNM3 plays a role in synapticvesicle recycling and is found in post-synaptic densities. B. Calabreseet al. (2015) Mol Cell Neurosci 68: 36-45; A M. Gonzalez-Jamett et al.(2014) Journal of Neurochemistry 128: 210-223. Genome wide associationstudies have implicated DNM3 as being linked to CNS disorders such asobsessive compulsive disorder. J. Costas et al. (2016) Transl Psychiatry6: e768.

Provided herein is a method of modulating dynamin 3 expressioncomprising contacting cortical neurons with 10-hydroxy-2-decenoic acid.

Provided herein is a method of modulating dynamin 3 expression in asubject comprising administering to the subject a pharmaceuticalcomposition comprising 10-hydroxy-2-decenoic acid, or a pharmaceuticallyacceptable salt thereof.

Provided herein is a method of modulating 5-hydroxytryptamine receptor2C expression comprising contacting cortical neurons with10-hydroxy-2-decenoic acid.

Provided herein is a method of modulating 5-hydroxytryptamine receptor2C expression in a subject comprising administering to the subject apharmaceutical composition comprising 10-hydroxy-2-decenoic acid, or apharmaceutically acceptable salt thereof.

Provided herein is a method of modulating both dynamin 3 expression and5-hydroxytryptamine receptor 2C expression comprising contactingcortical neurons with 10-hydroxy-2-decenoic acid.

Provided herein is a method of modulating both dynamin 3 expression and5-hydroxytryptamine receptor 2C expression in a subject comprisingadministering to the subject a pharmaceutical composition comprising10-hydroxy-2-decenoic acid, or a pharmaceutically acceptable saltthereof.

The term “mammal” as used herein includes humans, primates, livestockanimals (e.g. horses, cattle, sheep, pigs, donkeys), laboratory testanimals (e.g. mice, rats, guinea pigs), companion animals (e.g. dogs,cats) and captive wild animals (e.g. kangaroos, deer, foxes).Preferably, the mammal is a human.

For certain of the abovementioned conditions it is clear that themethods of the invention may be used prophylactically as well as for thealleviation of acute symptoms. Accordingly, references herein to“treatment” or the like are to be understood to include suchprophylactic treatment, as well as treatment of acute conditions.

The term “indicative”, as used herein, denotes an association oraffiliation of a subject closely to a group or population of subjectswho present, or likely to present, with the same or a similar clinicalmanifestations or response to the treatment. For example, the clinicalmanifestations of OCD are encompassed by symptoms of OCD. Furthermore,the clinical manifestations of anxiety disorder are encompassed bysymptoms of anxiety disorders.

One of skill in the art will be familiar with the difficulties inadministering traditional antipsychotic and antidepressant medications;including lag phases and heightened anxiety in the initial stages oftreatment before the antidepressant effects are seen. Thus, in certainembodiments, it is envisaged that 10-HDA, pharmaceutically acceptablesalts thereof or compositions comprising 10-HDA as described herein maybe administered to a person in need thereof as a substitute orreplacement for traditional medication. In other embodiments, it isenvisaged that 10-HDA, pharmaceutically acceptable salts thereof orcompositions comprising 10-HDA may be administered to a subject in needthereof as a supplement or adjunct to traditional medication. In stillother embodiments, it is envisaged that 10-HDA, or compositionscomprising 10-HDA, or a pharmaceutically acceptable salts thereof, maybe administered to a person in need thereof in the absence of adjuncttherapy. In still other embodiments, it is envisaged that 10-HDA,compositions comprising 10-HDA, or pharmaceutically acceptable saltsthereof, may be administered to a person in need thereof in conjunctionwith, or as an adjunct to, behavioural or cognitive therapies.

Replacing traditional medication with 10-HDA, compositions comprising10-HDA, or pharmaceutically acceptable salts thereof, may beadvantageous, particularly where the traditional medication isassociated with one or more adverse effects (e.g., sleepiness, tremors,anxiety, suicidal ideation, etc.). Examples of medication would be knownto those skilled in the art and include, but are not limited to,selective serotonin re-uptake inhibitors (S SRI), antipsychotics,antidepressants, lithium and other mood stabilisers.

In other embodiments, 10-HDA, compositions comprising 10-HDA, orpharmaceutically acceptable salts thereof are administered to a subjectin need thereof, together with traditional medication for a discreteperiod of time, to address symptoms such repetitive behaviours and/oranxiety, with the option of discontinuing treatment with the 10-HDAwhilst continuing with the traditional therapy. In still otherembodiments, the person in need thereof may be treated with 10-HDA,compositions comprising 10-HDA, or pharmaceutically acceptable saltsthereof and one or more traditional medications (administeredsequentially or in combination) for the duration of the treatmentperiod. Such combination therapy may be particularly useful, forexample, where an additive or synergistic therapeutic effect is desired.

“Treat”, “treating” or “treatment” with regard to a disorder or diseaserefers to alleviating or abrogating the cause and/or the effects of thedisorder or disease. As used herein, the terms “treat”, “treatment” and“treating” refer to the reduction or amelioration of the progression,severity and/or duration of condition, or the amelioration of one ormore symptoms (e.g., one or more discernible symptoms) of said condition(i.e., “managing” without “curing” the condition), resulting from theadministration of one or more therapies (e.g., one or more therapeuticagents such as a compound or composition of the invention). In specificembodiments, the terms “treat”; “treatment” and “treating” refer to theamelioration of at least one measurable physical parameter of acondition described herein. In other embodiments the terms “treat”,“treatment” and “treating” refer to the inhibition of the progression ofa condition described herein, either physically by, e.g., stabilizationof a discernible symptom or physiologically by, e.g., stabilization of aphysical parameter, or both.

The desired therapeutic activity, or effect, will typically depend onthe condition being treated. For example, where the subject is beingtreated for obsessive compulsive disorder, the therapeutic effect may bea reduction in at least one clinical symptom of obsessive compulsivedisorder, including, but not limited to repetitive behaviouraldisturbances. In the case where the subject is being treated for anxietydisorder, the therapeutic effect may be a reduction in at least oneclinical symptom of the anxiety disorder, including, but not limited to,reduction in anxiety or a reduction in sleep disturbance (i.e. improvedsleep patterns).

The terms “preventing” and “prophylaxis” as used herein refer toadministering a medicament beforehand to avert or forestall theappearance of one or more symptoms of a disease or disorder. The personof ordinary skill in the medical art recognizes that the term “prevent”is not an absolute term. In the medical art it is understood to refer tothe prophylactic administration of a drug to substantially diminish thelikelihood or seriousness of a condition, or symptom of the conditionand this is the sense intended in this disclosure. As used in a standardtext in the field, the Physician's Desk Reference, the terms “prevent”,“preventing” and “prevention” with regard to a disorder or disease,refer to averting the cause, effects, symptoms or progression of adisease or disorder prior to the disease or disorder fully manifestingitself

The compounds of the present invention are administered to the person inneed thereof in a treatment effective amount. In some embodiments, atreatment effective amount is a therapeutically effective amount or aprophylactically effective amount. The term “therapeutically effectiveamount” as used herein means that amount of an active compound thatelicits the biological or medicinal response in a tissue, system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor, or other clinician. The therapeutically effective amount of thecompound to be administered will be governed by such considerations, andis the minimum amount necessary to ameliorate, cure, or treat thedisease or disorder or one or more of its symptoms. The term“prophylactically effective amount” refers to an amount effective inpreventing or substantially lessening the chances of acquiring a diseaseor disorder or in reducing the severity of the disease or disorderbefore it is acquired or reducing the severity of one or more of itssymptoms before the symptoms develop. Roughly, prophylactic measures aredivided between primary prophylaxis (to prevent the development of adisease or symptom) and secondary prophylaxis (whereby the disease orsymptom has already developed and the patient is protected againstworsening of this process).

As used herein, the term “effective amount” relates to an amount ofcompound which, when administered according to a desired dosing regimen,provides the desired therapeutic activity. Dosing may occur at intervalsof minutes, hours, days, weeks, months or years or continuously over anyone of these periods. Suitable dosages lie within the range of about 0.1ng per kg of body weight to 100 g per kg of body weight per dosage. Thedosage may be in the range of 1 μg to 10 g per kg of body weight perdosage, such as is in the range of 1 mg to 1000 mg per kg of body weightper dosage. In one embodiment, the dosage may be in the range of 1 mg to500 mg per kg of body weight per dosage. In another embodiment, thedosage may be in the range of 1 mg to 250 mg per kg of body weight perdosage. In yet another embodiment, the dosage may be in the range of 1mg to 200 mg per kg of body weight per dosage, such as up to 50 mg perbody weight per dosage.

The terms “administer”, “administering” or “administration” in referenceto a compound, composition or formulation of the invention meansintroducing the compound into the system of the animal in need oftreatment. When a compound of the invention is provided in combinationwith one or more other active agents, “administration” and its variantsare each understood to include concurrent and/or sequential introductionof the compound and the other active agents.

In certain embodiments, an effective amount of a compound foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 4000 mg, about 0.0001 mg to about 3000mg, about 0.0001 mg to about 200 mg, about 0.001 mg to about 1500 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of compound per unit dosageform.

In certain embodiments, the extracts and/or compounds of the inventionmay be at dosage levels sufficient to deliver from about 0.001 mg/kg toabout 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, fromabout 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10mg/kg, and from about 1 mg/kg to about 25 mg/kg, of subject body weightper day, one or more times a day, to obtain the desired therapeuticeffect.

Suitable dosage amounts and dosing regimens can be determined by theattending physician and may depend on the particular condition beingtreated, the severity of the condition as well as the general age,health and weight of the subject. It will be appreciated that doseranges as described herein provide guidance for the administration ofprovided pharmaceutical compositions to an adult. The amount to beadministered to, for example, a child or an adolescent can be determinedby a medical practitioner or person skilled in the art and can be loweror the same as that administered to an adult.

Compounds of the present invention may be administered in a single doseor a series of doses. While it is possible for the compound to beadministered alone, in some embodiments it may be preferable to presentit as a composition, preferably as a pharmaceutical composition. Theformulation of such compositions is well known to those skilled in theart. Such a composition may contain any suitable carriers, diluents orexcipients. These include all conventional solvents, dispersion media,fillers, solid carriers, coatings, antifungal and antibacterial agents,dermal penetration agents, surfactants, isotonic and absorption agentsand the like. It will be understood that the compositions of theinvention may also include other supplementary physiologically activeagents.

The compounds and associated pharmaceutical compositions of the presentinvention may be used in combination therapy with one or more additionaltherapeutic agents. For combination treatment with more than one activeagent, where the active agents are in separate dosage formulations, theactive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of the other agent.

When co-administered with other agents, e.g., when co-administered withanother antipsychotic, anticonvulsant or antidepressant medication, an“effective amount” of the second agent will depend on the type of drugused. Suitable dosages are known for approved agents and can be adjustedby a person skilled in the art according to the condition of thesubject, the type of condition(s) being treated and the amount of acompound, extract or composition being used. In cases where no amount isexpressly noted, an effective amount should be assumed. For example,compounds described herein can be administered to a subject in a dosagerange from between about 0.01 to about 10,000 mg/kg body weight/day,about 0.01 to about 5000 mg/kg body weight/day, about 0.01 to about 3000mg/kg body weight/day, about 0.01 to about 1000 mg/kg body weight/day,about 0.01 to about 500 mg/kg body weight/day, about 0.01 to about 300mg/kg body weight/day, about 0.01 to about 100 mg/kg body weight/day.

The phrase “combination therapy” as used herein, is understood to referto administration of an effective amount, using a first amount of10-HDA, a composition comprising 10-HDA or a pharmaceutically acceptablesalt thereof as described herein, and a second amount of an additionalsuitable therapeutic agent.

In certain embodiments, 10-HDA, or a composition comprising 10-HDA asdescribed herein, or a pharmaceutically acceptable salt thereof, and theadditional therapeutic agent, are each administered in an effectiveamount (i.e., each in an amount which would be therapeutically effectiveif administered alone). In other embodiments, 10-HDA, or a compositioncomprising 10-HDA as described herein, or a pharmaceutically acceptablesalt thereof, and the additional therapeutic agent are each administeredin an amount which alone does not provide a therapeutic effect (asub-therapeutic dose). In yet other embodiments, 10-HDA, or acomposition comprising 10-HDA as described herein, or a pharmaceuticallyacceptable salt thereof, can be administered in an effective amount,while the additional therapeutic agent is administered in asub-therapeutic dose. In still other embodiments, 10-HDA, or acomposition comprising 10-HDA as described herein, or a pharmaceuticallyacceptable salt thereof, can be administered in a sub-therapeutic dose,while the additional therapeutic agent is administered in an effectiveamount.

As used herein, the terms “in combination” or “co-administration” can beused interchangeably to refer to the use of more than one therapy (e.g.,one or more prophylactic and/or therapeutic agents). The use of theterms does not restrict the order in which therapies (e.g., prophylacticand/or therapeutic agents) are administered to a person in need thereof.

Co-administration encompasses administration of the first and secondamounts of therapeutic compounds in an essentially simultaneous manner,such as in a single pharmaceutical composition, for example, capsule ortablet having a fixed ratio of first and second amounts, or in multiple,separate capsules or tablets for each. In addition, suchco-administration also encompasses use of each compound in a sequentialmanner in either order. When co-administration involves the separateadministration of the first amount of 10-HDA, or a compositioncomprising 10-HDA, as described herein, or a pharmaceutically acceptablesalt thereof, and a second amount of an additional therapeutic agent,they are administered sufficiently close in time to have the desiredtherapeutic effect. For example, the period of time between eachadministration which can result in the desired therapeutic effect, canrange from minutes to hours and can be determined taking into accountthe properties of each compound such as potency, solubility,bioavailability, plasma half-life, and kinetic profile. For example,10-HDA, or a composition comprising 10-HDA as described herein, or apharmaceutically acceptable salt thereof, and the second therapeuticagent can be administered in any order within about 24 hours of eachother, within about 16 hours of each other, within about 8 hours of eachother, within about 4 hours of each other, within about 1 hour of eachother or within about 30 minutes of each other.

10-HDA, or a composition comprising 10-HDA, or a pharmaceuticallyacceptable salt thereof, in accordance with the invention may beadministered by any route, including enteral (e.g., oral), parenteral,intravenous, intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specifically,contemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general, the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration). In particular embodiments, 10-HDA, ora composition comprising 10-HDA of the present invention areadministered orally.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound(s), mode ofadministration, and the like. The desired dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the desired dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations).

Where a carrier is used, the carrier must be pharmaceutically“acceptable” in the sense of being compatible with the other ingredientsof the composition and not injurious to the subject. Compositionsinclude those suitable for oral, rectal, nasal, topical (includingbuccal and sublingual), vaginal or parental (including subcutaneous,intramuscular, intravenous, and intradermal) administration. Thecompositions may conveniently be presented in unit dosage form and maybe prepared by any methods well known in the art of pharmacy. Suchmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients. In general, the compositions are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then if necessaryshaping the product.

Pharmaceutically acceptable excipients include any and all solvents,diluents, or other liquid vehicles, dispersions, suspension aids,surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants, and the like, assuited to the particular dosage form desired. General considerations informulation and/or manufacture of pharmaceutical compositions agents canbe found, for example, in Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), andRemington: The Science and Practice of Pharmacy, 21st Edition(Lippincott Williams & Wilkins, 2005).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound of the presentinvention (the “active ingredient”) into association with a carrierand/or one or more other accessory ingredients, and then, if necessaryand/or desirable, shaping and/or packaging the product into a desiredsingle- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is a discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

In some embodiments, where 10-HDA of the present invention is for oraladministration, it may be prepared as discrete units such as capsules,sachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion ora water-in-oil liquid emulsion. The 10-HDA may also be presented as abolus, electuary or paste.

In some embodiments, where the 10-HDA is formulated as a tablet, thetablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder (e.g., inert diluent, preservative disintegrant (e.g., sodiumstarch glycolate, cross-linked polyvinyl pyrrolidone, cross-linkedsodium carboxymethyl cellulose) surface-active or dispersing agent.Moulded tablets may be made by moulding in a suitable machine a mixtureof the powdered compound moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and may be formulated so asto provide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile. Tablets may optionally beprovided with an enteric coating, to provide release in parts of the gutother than the stomach.

In some embodiments, the 10-HDA, or compositions comprising 10-HDA, ofthe present invention may be in micro-encapsulated form with one or moreexcipients. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings, release controlling coatings and other coatings well known inthe pharmaceutical formulating art. In such solid dosage forms theactive ingredient can be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may comprise, as isnormal practice, additional substances other than inert diluents, e.g.,tableting lubricants and other tableting aids such a magnesium stearateand microcrystalline cellulose. In the case of capsules, tablets, andpills, the dosage forms may comprise buffering agents. They mayoptionally comprise opacifying agents and can be of a composition thatthey release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions which can be used include polymericsubstances and waxes.

In some embodiments, where the 10-HDA of the present invention is to beadministered as a liquid dosage form for oral and parenteraladministration, such a dosage form may include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active ingredients, the liquid dosage formsmay comprise inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (e.g., cottonseed, groundnut, com, germ,olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof. Besides inert diluents, the oral compositions can includeadjuvants such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents. In certain embodiments forparenteral administration, the 10-HDA of the invention is mixed withsolubilizing agents such as Cremophor™, alcohols, oils, modified oils,glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

In some embodiments, where the 10-HDA, or a composition comprising10-HDA, of the present invention is to be administered topically in themouth, suitable dosage forms may include lozenges comprising the activeingredient in a flavoured base, usually sucrose and acacia or tragacanthgum; pastilles comprising the active ingredient in an inert basis suchas gelatine and glycerin, or sucrose and acacia gum; and mouthwashescomprising the active ingredient in a suitable liquid carrier.

In some embodiments, where the 10-HDA, or composition comprising 10-HDA,of the present invention is to be administered topically to the skin,suitable dosage forms may include the dissolving or suspending theextract or component compound in any suitable carrier or base and may bein the form of lotions, gel, creams, pastes, ointments and the like.Suitable carriers include mineral oil, propylene glycol,polyoxyethylene, polyoxypropylene, emulsifying wax,sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol, and water. Transdermalpatches may also be used to administer the extract or component compoundof the invention.

In some embodiments, the 10-HDA, or composition comprising 10-HDA, ofthe present invention is for rectal administration, suitable dosageforms may include a suppository with a suitable base comprising, forexample, cocoa butter, glycerin, gelatine or polyethylene glycol.

In some embodiments, where the 10-HDA, or composition comprising 10-HDA,of the present invention is for vaginal administration, suitable dosageforms may include pessaries, tampons, creams, gels, pastes, foams orspray formulations containing in addition to the active ingredient suchcarriers as are known in the art to be appropriate.

In some embodiments, where the 10-HDA, or composition comprising 10-HDA,of the present invention is for parenteral administration, suitabledosage forms may include aqueous and non-aqueous isotonic sterileinjection solutions which may contain anti-oxidants, buffers,bactericides and solutes which render the composition isotonic with theblood of the intended recipient; and aqueous and non-aqueous sterilesuspensions which may include suspending agents and thickening agents.The compound may be presented in unit-dose or multi-dose sealedcontainers, for example, ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of thesterile liquid carrier, for example water for injections, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described. An injectable preparation can be a sterileinjectable solution, suspension or emulsion in a nontoxic parenterallyacceptable diluent or solvent, for example, as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that can beemployed are water, Ringer's solution, U.S.P. and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose any blandfixed oil can be employed including synthetic mono- or diglycerides. Inaddition, fatty acids such as oleic acid are used in the preparation ofinjectables. The injectable formulations can be sterilized, for example,by filtration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In certain embodiments, unit dosage compositions are those containing adaily dose or unit, daily sub-dose, as herein above described, or anappropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the active agent 10-HDA,compositions comprising 10-HDA of this invention may include otheragents conventional in the art having regard to the type of compositionin question, for example, those suitable for oral administration mayinclude such further agents as binders, sweeteners, thickeners,flavouring agents disintegrating agents, coating agents, preservatives,lubricants and/or time delay agents. Suitable sweeteners includesucrose, lactose, glucose, aspartame or saccharine. Suitabledisintegrating agents include cornstarch, methylcellulose,polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.Suitable flavouring agents include peppermint oil, oil of wintergreen,cherry, orange or raspberry flavouring. Suitable coating agents includepolymers or copolymers of acrylic acid and/or methacrylic acid and/ortheir esters, waxes, fatty alcohols, zein, shellac or gluten. Suitablepreservatives include sodium benzoate, vitamin E, alpha-tocopherol,ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.Suitable lubricants include magnesium stearate, stearic acid, sodiumoleate, sodium chloride or talc. Suitable time delay agents includeglycerylmonostearate or glyceryldistearate.

The phrase “pharmaceutically acceptable salt,” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a providedcompound. For use in medicine, the salts of the provided compounds willbe pharmaceutically acceptable salts. Other salts may, however, beuseful in the preparation of provided compounds or of theirpharmaceutically acceptable salts. Pharmaceutically acceptable salts arewell known in the art. For example, Berge et al., describepharmaceutically acceptable salts in detail in J Pharm. Sci. (1977) 66:1-19, incorporated herein by reference in its entirety. Apharmaceutically acceptable salt involves the inclusion of anothermolecule such as an acetate ion, a succinate ion or other counter ion.The counter ion may be any organic or inorganic moiety that stabilizesthe charge on the parent compound. Furthermore, a pharmaceuticallyacceptable salt may have more than one charged atom in its structure.When multiple charged atoms are present in the parent drug, itspharmaceutically acceptable salts will have multiple counter ions andthese can be several instances of the same counter ion or differentcounter ions. Hence, a pharmaceutically acceptable salt can have one ormore charged atoms in the parent compound and/or one or more counterions.

Pharmaceutically acceptable salts of the compounds described hereininclude those derived from suitable inorganic and organic acids andbases. In some embodiments, the salts can be prepared in situ during thefinal isolation and purification of the compounds. In other embodimentsthe salts can be prepared from the free form of the compound in aseparate synthetic step.

When a provided compound is acidic or contains a sufficiently acidicbioisostere, suitable “pharmaceutically acceptable salts” refers tosalts prepared form pharmaceutically acceptable non-toxic basesincluding inorganic bases and organic bases. Salts derived frominorganic bases include aluminium, ammonium, calcium, copper, ferric,ferrous, lithium, magnesium, manganic salts, manganous, potassium,sodium, zinc and the like. Particular embodiments include ammonium,calcium, magnesium, potassium and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylaminetripropylamine, tromethamineand the like. Quarternary ammonium salts such as N⁺(C₁₋₄ alkyl)₄ arealso included.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berge et al., “Pharmaceutical Salts,” J Pharm. Sci.,1977:66: 1-19.

The formulations of 10-HDA, or compositions comprising 10-HDA, describedherein may be contained in a kit. The kit may include single or multipledoses of two or more agents, each packaged or formulated individually,or single or multiple doses of two or more agents packaged or formulatedin combination. Thus, one or more agents can be present in firstcontainer, and the kit can optionally include one or more agents in asecond container. The container or containers are placed within apackage, and the package can optionally include administration or dosageinstructions. A kit can include additional components such as syringesor other means for administering the agents as well as diluents or othermeans for formulation. Thus, the kits can comprise: a) a pharmaceuticalcomposition comprising a compound described herein and apharmaceutically acceptable carrier, vehicle or diluent; and b) acontainer or packaging. The kits may optionally comprise instructionsdescribing a method of using the pharmaceutical compositions in one ormore of the methods described herein (e.g. preventing or treating one ormore of the diseases and disorders described herein). The kit mayoptionally comprise a second pharmaceutical composition comprising oneor more additional agents described herein for co therapy use, apharmaceutically acceptable carrier, vehicle or diluent. Thepharmaceutical composition comprising 10-HDA and the secondpharmaceutical composition contained in the kit may be optionallycombined in the same pharmaceutical composition.

A kit includes a container or packaging for containing thepharmaceutical compositions and may also include divided containers suchas a divided bottle or a divided foil packet. The container can be, forexample a paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.It is feasible that more than one container can be used together in asingle package to market a single dosage form. For example, tablets maybe contained in a bottle which is in turn contained within a box.

An example of a kit is a so-called blister pack. Blister packs are wellknown in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of individual tabletsor capsules to be packed or may have the size and shape to accommodatemultiple tablets and/or capsules to be packed. Next, the tablets orcapsules are placed in the recesses accordingly and the sheet ofrelatively stiff material is sealed against the plastic foil at the faceof the foil which is opposite from the direction in which the recesseswere formed. As a result, the tablets or capsules are individuallysealed or collectively sealed, as desired, in the recesses between theplastic foil and the sheet. Preferably the strength of the sheet is suchthat the tablets or capsules can be removed from the blister pack bymanually applying pressure on the recesses whereby an opening is formedin the sheet at the place of the recess. The tablet or capsule can thenbe removed via said opening.

It may be desirable to provide written memory aid containing informationand/or instructions for the physician, pharmacist or subject regardingwhen the medication is to be taken. A “daily dose” can be a singletablet or capsule or several tablets or capsules to be taken on a givenday. When the kit contains separate compositions, a daily dose of one ormore compositions of the kit can consist of one tablet or capsule whilea daily dose of another or more compositions of the kit can consist ofseveral tablets or capsules. A kit can take the form of a dispenserdesigned to dispense the daily doses one at a time in the order of theirintended use. The dispenser can be equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter which indicates the number of dailydoses that have been dispensed. Another example of such a memory-aid isa battery-powered micro-chip memory coupled with a liquid crystalreadout, or audible reminder signal which, for example, reads out thedate that the last daily dose has been taken and/or reminds one when thenext dose is to be taken.

It will be appreciated that any compound that is a prodrug of 10-HDA, isalso within the scope and spirit of the invention. The term “pro-drug”is used in its broadest sense and encompasses those derivatives that areconverted in vivo to the compounds of the invention. Such derivativeswould readily occur to those skilled in the art.

Furthermore, it is recognised that 10-HDA may be in crystalline formeither as the free compound or as a solvate (e.g., hydrates) and it isintended that both forms are within the scope of the present invention.Methods of salvation are generally known within the art.

It is further recognised that in light of its structure, 10-HDA inaccordance with the present invention may be capable of undergoingtautomerism. Accordingly, all possible tautomers of 10-HDA of thepresent invention fall within the scope and spirit of the invention.

As used herein, the term “derived from” shall be taken to indicate thata particular integer or group of integers has originated from thespecies specified, but has not necessarily been obtained directly fromthe specified source. For example, it is understood that 10-HDA may haveoriginated from royal jelly, but has not necessarily been obtaineddirectly from the specified source. Further, as used herein the singularforms of “a”, “and” and “the” include plural referents unless thecontext clearly dictates otherwise.

Those skilled in the art will be aware that the invention describedherein is subject to variations and modifications other than thosespecifically described. It is to be understood that the inventiondescribed herein includes all such variations and modifications. Theinvention also includes all such steps, features, methods, compositionsand compounds referred to or indicated in this specification,individually or collectively, and any and all combinations of any two ormore of said steps or features.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

Certain embodiments of the invention will now be described withreference to the following examples which are intended for the purposeof illustration only and are not intended to limit the scope of thegenerality hereinbefore described.

EXAMPLES Example 1: In Vivo Mouse Models

Aromatase is expressed in high levels in the mouse medial amygdala andthe same region is activated by interaction with a stranger mouse. Inhumans, aromatase is also highly expressed in the amygdala and fMRIstudies suggest that the amygdala is less activated in people with OCDthan controls. It was postulated that an Aromatase Knockout mouse (ArKO)model may exhibit behavioural phenotypes reflective of some of the keydiagnostic behaviours and symptoms of OCD and anxiety disorder,including, for example OCD-like behavioural disturbances, such asrepetitive behaviours.

Accordingly, an aromatase deficient mouse model (ArKO) was developedwhich presents the core OCD and anxiety disorder-like features,including social interaction deficit (FIG. I; A and B), compulsive wheelrunning (FIG. 2 A to D) and compulsive grooming (FIG. 3 C to F). Theresults described in FIG. 2 and FIG. 3 have been published at Hill et.al. Biol. Psychiatry (2007) 61:359-366.

Specifically, the inventors have found that the lack of a normalfunctioning aromatase will precipitate the following OCD-likebehavioural disturbances in the male ArKO (aromatase knockout) mouse,but not in the female ArKO mouse:

-   -   i) Abnormal Social interaction (FIG. 1A): Juvenile (4 week-old)        male ArKO mice were found to spend significantly less time        investigating the stranger mouse than wild-type male mouse (WT).        Conversely, the female ArKO and WT mice were found to spend        similar amounts of time with the stranger mouse.    -   ii) Ultrasonic vocalization deficit (Fig. IB): Male ArKO 9-day        old pups were found to vocalise significantly less than male WT        litter mates when separated from their litters    -   iii) Compulsive wheel-running: Male ArKO mice were also found to        spend significantly more time on the running wheel when compared        with WT and female ArKO mice (FIG. 2).    -   iv) Compulsive grooming: Male ArKO mice were found to groom more        frequently (FIG. 3C) and for longer periods of time (FIG. 3D),        when compared with WT and female ArKO mice. Specifically, the        grooming activity of each animal was analysed for 20 min after        administration of water mist spray (a trigger for grooming).        Male ArKO mice exhibited significantly (p<0.05) heightened        grooming activity in terms of frequency of initiation and        duration of grooming. Compulsive grooming observed in ArKO        represents an OCD-like repetitive behavioural disturbance in        OCD-patients.

Example 2: In Vivo Mouse Model Treated with 10-HDA

ArKO mice exhibiting behavioural phenotypes reflective of some of thekey diagnostic behaviours and symptoms of OCD and anxiety disorder,including repetitive behaviours such as compulsive grooming, wereadministered 10-HDA (FIG. 4). Specifically, male 3 month-old ArKO mice(n=5) were injected daily with 10-HDA (500 μg/kg) for 1 week. Similarlyto Example 1 (see above), water mist spray triggered grooming wasassessed before and after administration of 10-HDA treatment. Duringgrooming assessment, each mouse was subjected to two squirts of sterilewater mist spray and its grooming activity was recorded for 10 minimmediately after the mist spray. Grooming duration was analyzedstatistically by paired t test. A significant reduction in duration ofgrooming was observed after administration of 10-HDA to the ArKO mice(p=0.0363). Further grooming assessment was performed 5 days after thelast administration of 10-HDA. After the withdrawal period groomingduration was found to return to pre-treatment levels (FIG. 4).

Example 3: Next Generation Sequencing of Primary Cortical NeuronsHarvested from Mice

Foetal cortices of C57Black 6 mice (gestational days 15) weremicro-dissected and subjected to trypsin digestion and mechanicaltrituration and centrifugation. The pelleted cells were resuspended inNeurobasal™ medium (NBM) containing 2.5% B-27 supplement, 1% penicillin,1% streptomycin, 0.25% GlutaMAX-1 supplement and 10% dialysed foetalcalf serum. Cells were seeded on poly-d-lysine (100 μg/ml) coated12-well plates to a density of 400×105 cells/cm². Cultures weremaintained at 37° C. in a humidified 5% CO₂ and 95% air incubator andwere subsequently cultured after day 1 in serum-free medium. After 24hours, primary cortical neurons were treated with DMSO or 1 mM 10-HDA,and harvested for total RNA preparation on Day 7 for subsequent NextGeneration Sequencing (RNAseq). There were 4 biological repeats, i.e. 4individual dams; 4 technical repeats per biological repeat, i.e. 4plates per individual mouse and 3 wells per treatment.

Samples were kept cold during the harvesting of cortical neurons for RNApreparation. Culture medium was removed by aspiration, and 100 μL ofice-cold Cell Disruption Buffer (Paris Kit, Ambion®) added per well.i.e. 300 μL for ≥10⁶ cells. The cells were lysed immediately uponexposure to the Cell Disruption Buffer; wells were scraped with wide endof 200 μl RNA free pipette tip and lysates were then transferred into a1.7 ml Eppendorf tube. To completely lyse the cells, the lysate waspipetted vigorously till a homogenous lysate was obtained. All lysateswere stored at −80° C.

Total RNA was extracted from each sample using the PARIS kit (Ambion).The quality of RNA was assessed by LabChip® (Perkin Elmer). Librarieswere generated from the total RNA using SureSelect Strand Specific RNALibrary Prep for Illumina Multiplexed Sequencing (Agilent Technologies).The libraries were sequenced with 50 bp single end reads using IlluminaHiseq and subjected to bioinformatic analyses. Sequencing data wereassessed (FastQC) and aligned to mouse genome using Subjunc alignerwithin the Subread package. Sequencing data was summarised into Readsper transcript using Feature counts and the Gencode gene models for themouse genome build. Normalisation and statistical analysis on the countdata was performed using EdgeR and scaled using trimmed mean of M-values(TMM).

Next Generation Sequencing data showed that 10-HDA significantlyupregulated transcript expression levels of dynamin 3 and5-hydroxytryptamine (serotonin) receptor 2C (FIG. 5). Both genes areimplicated in Obsessive Compulsive Disorders (Transl. Psychiatry. 2016Mar. 29; 6:e768, Eur. Neuropsychopharmacol. 2000 May 10(3): 205-8,Expert Opin Investig Drugs. 1998 October; 7(10):1587-99, Physiol. Behav.2003 April; 78(4-5):641-9).

1.-31. (canceled)
 32. A method for the treatment of obsessive compulsivedisorder, comprising administering to a mammal in need thereof aneffective amount of 10-hydroxy-2-decenoic acid or a pharmaceuticallyacceptable salt thereof.
 33. The method according to claim 32,comprising administering an effective amount of trans10-hydroxy-2-decenoic acid or a pharmaceutically acceptable saltthereof.
 34. The method according to claim 32, comprising administeringan effective amount of cis 10-hydroxy-2-decenoic acid or apharmaceutically acceptable salt thereof.
 35. The method according toclaim 32, comprising administering an effective amount of a racemicmixture of trans and cis 10-hydroxy-2-decenoic acid or pharmaceuticallyacceptable salts thereof.
 36. The method according to claim 32, whereinthe obsessive compulsive disorder is selected from the group consistingof obsessive compulsive disorder (OCD), body dysmorphic disorder,hoarding disorder, trichotillomania, excoriation disorder,substance/medication-induced obsessive-compulsive, and unspecifiedobsessive-compulsive disorder.
 37. The method according to claim 32,wherein the treatment alleviates one or more behavioural disturbancesselected from obsessions, compulsions, and repetitive behaviouralpatterns.
 38. The method according to claim 32, wherein the10-hydroxy-2-decenoic acid or a pharmaceutically acceptable salt thereofis administered as a composition.
 39. The method according to claim 38,wherein the composition comprises royal jelly, an extract of royaljelly, or a composition derived from royal jelly.
 40. The methodaccording to claim 32, wherein the 10-hydroxy-2-decenoic acid or apharmaceutically acceptable salt thereof is administered in a dosage inthe range of 0.01 to 6000 mg/day, 0.1 to 5000 mg/day, 1 to 4000 mg/day,10 to 3000 mg/day, 100 to 2000 mg/day, or 500 to 1500 mg/day.
 41. Themethod according to claim 32, wherein the 10-hydroxy-2-decenoic acid ora pharmaceutically acceptable salt thereof is administered in a dosageselected from 0.5 mg/day, 1 mg/day, 5 mg/day, 10 mg/day, 50 mg/day, 100mg/day, 250 mg/day, 500 mg/day, 750 mg/day, 1000 mg/day, 1500 mg/day,and 2000 mg/day.
 42. The method according to claim 32, wherein themammal is a human.